OLEYL PHOSPHOCHOLINE CONTAINING GRANULATES

Abstract

The present invention relates to tablet dosage formulations of oleyl phosphocholine for oral administration and the processes for their preparation. Specifically, the present invention provides a process for preparing an oleyl phosphocholine containing granulate. The present invention further provides a process for preparing a pharmaceutical dosage formulation, such as a tablet or a capsule, comprising the oleyl phosphocholine containing granulate. The invention further provides any intermediate and/or en product resulting from these steps and processes.

Claims

1. A process for making an olelyl phosphocholine (OlPC) containing granulate, said process comprises the consecutive steps of: a) preparing a mixture of olelyl phosphocholine, an anti-oxidant, a filler and, optionally, a granulation liquid and/or one or more further granulation excipients; b) processing the mixture prepared in step a) into a dry granulate; and c) milling the granulate produced in step b); characterized in that the antioxidant is vitamin E, vitamin E TPGS, apha-tocopherol acetate and/or alpha-tocopherol.

2. A process according to claim 1, wherein the filler is selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnesium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol, silicon dioxide, and mixtures thereof.

3. A process according to claim 1, wherein step b) comprises a melt-agglomeration process, preferably a hot-melt extrusion process.

4. A process according to claim 4, wherein no solvent is added during any one of steps a), b) and c).

5. A process according to claim 1, wherein step b) comprises a wet granulation process, preferably a high-shear wet granulation process.

6. A process according to claim 5, wherein step a) comprises: a1) providing a dry powder (blend) of the filler and optional further granulation excipients; a2) preparing a solution of the OLPC and anti-oxidant in the granulation liquid; and adding to the dry powder (blend) of step a1), the solution prepared in step a2).

7. A process according to claim 1, wherein step b) does not comprise a hot-melt extrusion process wherein no solvent is added during the process.

8. An olelyl phosphocholine (OlPC) containing granulate obtainable by a process as defined in claim 1.

9. A pharmaceutical formulation comprising the OLPC containing granulate of claim 8.

10. A pharmaceutical formulation according to claim 9, wherein the formulation is selected from the group consisting a tablet, a filled capsule, a powder,

11. A process for preparing an OLPC containing capsule dosage formulation comprising: I. a process for making an OlPC containing granulate according to claim 1; II. optionally mixing the OlPC containing granulate with one or more excipients; III. filling of the mixture produced in step II) into hollow capsules.

12. A capsule dosage formulation obtainable by the process according to claim 11.

13. A process for preparing a tablet dosage formulation comprising: i. a process for making an OlPC containing granulate according to claim 1; ii. preparing a compression mixture by mixing the OlPC containing granulate with compression excipients, iii. wherein said compression excipients comprise at least a filler and a lubricant, and optionally a binder and/or a disintegrant; iv. compressing the mixture produced in step ii) into a tablet; and, optionally v. coating the compressed tablet obtained in step iii).

14. A tablet dosage formulation obtainable by the process according to claim 13.

15. A dosage formulation according to claims 12, wherein, if said dosage formulation is stored for at least 24 months at a temperature of 30° C. and at a relative humidity of 75%, the concentration of each active pharmaceutical ingredient in said dosage formulation does not change by more than 2.5 weight percent, preferably by no more than 1 weight percent; and each active pharmaceutical ingredient in said dosage formulation has a stable dissolution release profile.

16.-17. (canceled)

18. A method for the treatment of a parasitic diseases, preferably a parasitic disease selected from the group consisting of leishmaniasis, chagas, malaria and cancer, the method comprising administering the dosage formulation according to claim 12 to a subject in need thereof.

Description

LEGEND OF THE FIGURES

[0168] FIG. 1: Process for preparing the tablet core of the tablet dosage formulation in Example 1.

EXAMPLES

[0169] The following examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way.

Example 1

Granulate

[0170] In this example a granulate according to this application is produced, using hot melt extrusion. The composition of this milled extrudate is given in Table 1.

TABLE-US-00001 TABLE 1 Composition of milled extrudate % in the milled extrudate mass (157.730 mg (mg per milled extrudate tablet) per tablet) API oleyl phosphocholine 50.000 31.700 Granulation alpha tocopherolacetate 1.000 0.634 excipient microcrystalline cellulose 49.000 31.066 macrogol 6000 50.000 31.700 sodium croscarmellose 7.730 4.901 Sum 157.730 100.000

Example 2

Tablet Dosage Formulation

[0171] In this example is provided a tablet dosage formulation prepared via a process for preparing a tablet dosage formulation according to the invention. In this process, the milled extrudate as described in Example 1 was an intermediate.

[0172] The composition of the compression mixture in this example, prepared as an intermediate during the process for preparing a tablet dosage formulation according to the invention, is given in Table 2.

[0173] The composition of the tablet dosage formulation in this example is given in Table 3. The composition of the tablet coating of the tablet dosage formulation in this example is given in Table 4.

[0174] The tablet core of the tablet dosage formulation in this example was prepared via the process steps as described in FIG. 1.

TABLE-US-00002 TABLE 2 Composition of the compression mixture mass (mg per tablet) Compression lactose monohydrate 97.920 excipient microcrystalline cellulose 47.250 sodium croscarmellose 9.350 magnesium stearate 3.150 Sum 157.670 Milled extrudate 157.730 Compression 315.400 mixture

TABLE-US-00003 TABLE 3 Composition of tablet dosage formulation % in the tablet dosage mass formulation (mg per (557.700 mg tablet) per tablet) API oleyl phosphocholine 50.000 8.965 Excipient alpha tocopherolacetate 1.000 0.180 microcrystalline cellulose 96.250 17.258 macrogo 16000 50.000 8.965 sodium croscarmellose 17.080 3.062 lactose monohydrate 97.920 17.558 magnesium stearate 3.150 0.565 Coating 242.300 43.446 Sum 557.700 100.00

TABLE-US-00004 TABLE 4 Composition of the tablet coating mass (mg per tablet) Seal coating 3.976 Talc 0.904 Sugar coating 19.605 Talc-calcium mixture 31.679 Sugar coating 129.870 Colour coating 56.112 Motanylglycolwax 0.160 Sum 234.600

Example 3

Stability of a Tablet Dosage Formulation

[0175] The change of the concentration of oleyl phosphocholine in the tablet dosage formulation described in Example 2 upon storage under different conditions can be found in Table 5.

TABLE-US-00005 TABLE 5 Change of oleyl phosphocholine concentration OIPC concentration in the tablet dosage formulation Conditions (mg/tablet) after X months of storage T RH X = 0 X = 3 X = 6 X = 18 X = 24 X = 36 25° C. 60% 50.2 48.1 48.1 49.15 47.10 50.14 30° C. 75% 50.2 47.5 49.7 50.17 47.46 49.30 40° C. 75% 50.2 48.9 49.9

Example 4

Dissolution of Oleyl Phosphocholine

[0176] The dissolution of oleyl phosphocholine comprised in the tablet dosage formulation described in Example 2, which has been stored for different time periods (18 months, 24 months, 36 months) under different conditions, has been determined by the European Pharmacopoeia 2.9.3 standard dissolution test after 60 minutes. The results can be found in Table 6.

TABLE-US-00006 TABLE 6 Dissolution of oleyl phosphocholine concentration Dissolved weight percentage of oleyl phosphocholine after 60 minutes, relative to the tablet dosage formulation Conditions storage of storage of storage of T RH 18 months 24 months 36 months 25° C. 60% 78.4 83.2 96.4 30° C. 75% 89.9 80.9 83.3